Particles can be prepared by adding a solubilized compound, i.e. a compound dissolved in one or more solvents, to an anti-solvent. Such a process can be used to prepare particles in many different size distributions. A key drawback of such a process, however, is the entrapment of solvent and/or anti-solvent within and/or on the surface of the particles.
Removal of solvent from the particles typically involves washing of the particles with additional amounts of anti-solvent, which unfortunately results in saturation of the particles with anti-solvent, unless the anti-solvent is very volatile. For this reason, supercritical fluid (SCF) is often employed as the anti-solvent. SCF, in particular supercritical carbon dioxide, is very volatile and easily removed from the particles. Solvents, however, are less volatile than the SCF and thus are more difficult to remove.
Due to the extreme volatility of supercritical carbon dioxide, it is a challenge to effectively harvest particles from it unless the particles are first physically separated from it. Filtration is the most common approach used for affecting separation of particles from SCF while still permitting repeated wash cycles. When microparticles or nanoparticles are being processed, however, it is more difficult to separate the particles from the SCF due to fouling of filters, and it is difficult to unfoul filters when a process is running. Moreover, typical filters used to separate the particles are flat dead-end filters, which must be opened to harvest the particles. These challenges make continuous processing and harvesting of particles extremely difficult to achieve.
Numerous such processes and apparatuses for the processing of drug, mineral, metal or toner particles in supercritical fluid have been disclosed: U.S. Pat. Nos. 6,270,732, 5,584,913, 5,571,299, 5,460,701, 4,881,722, 5,874,029, 5,874,684, 6,113,795, 5,961,835, 5,527,466, 7,740,775, 7,635,442, 7,175,886, 7,250,152, 7,279,181, 7,449,136, 6,916,389, 7,291,296, 7,332,111, 7,150,766, 6,860,907, 6,440,337, 6,830,714, 6,620,351, 5,981,474, 8,323,685, 8,323,615, 8,215,489, 6,998,051, 5,864,923, 7,455,797, U.S. 20020010982, and U.S. 20010051118. These systems typically employ dead-end filters, cyclones, bag filters, depth filters or other such types. Many of these systems cannot be operated continually since they require halting of operations and opening of components in the process stream in order to remove particles. An important aspect of supercritical fluid based processes is that supercritical pressure and temperature must be maintained throughout the filtration step to avoid phase separation of solvent from the SCF and avoid redissolution of the solute back into the solvent. This is particularly difficult to achieve when particle formation is conducted continuously.
A need remains for improved equipment and processes for the preparation, harvesting and collection of small particles, especially those prepared in SCF. In particular, there remains a need for a higher throughput system that can be operated continuously or semi-continuously and that permits particle collection with minimal or no cessation of the particle formation step.